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D P de Bono

Publications and source records attributed to D P de Bono.

At least 19 recordsLinked to original sources
PubMed2001

Plasminogen activator and plasminogen activator inhibitor gene expression in human saphenous vein organ culture.

We describe the expression of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) in saphenous vein culture. Smooth muscle cells (SMC) are quiescent in fresh tissue, whereas these cells acquire a proliferating phenotype when venous segments are cultured in the presence of serum. t-PA and PAI-1 were localized immunohistochemically and quantified using biochemical techniques. t-PA and PAI-1 mRNA was quantified by reverse transcription polymerase chain reaction (RT--PCR) assay. Immunostaining showed an increase in the positivity of proliferating cell nuclear antigen (PCNA) from 10-day tissue culture. Tissue sections from fresh vein showed minimal t-PA and maximal PAI-1 immunostaining. In contrast, 10-day cultures showed an increase in t-PA and a decline in PAI-1 staining. Biochemical analysis revealed a 118% increase in t-PA and a 50% decrease in PAI-1 antigen levels from 10-day tissue cultures. RT--PCR demonstrated that the mRNA encoding t-PA increased, while PAI-1 decreased after 10 days of culture. In conclusion, venous culture showed an up-regulation of t-PA and a repression of PAI-1 gene expression during SMC proliferation in the vessel wall. The PAI-1 repression observed in venous culture is in contrast to the situation observed in human atheroma. A shift in the t-PA/PAI-1 balance may have a role in vascular remodeling.

Blotting, Western↗
PubMed2000

Galectin 1 is involved in vascular smooth muscle cell proliferation.

OBJECTIVE: Smooth muscle cell (SMC) migration and proliferation are the key steps in the development of atherosclerosis and restenosis. Matricellular proteins have been implicated in cell adhesion, migration and proliferation. Here we investigated the role of the matricellular protein galectin-1 (Gal-1), a beta-galactoside-binding lectin, in SMC proliferation in atheroma and DNA synthesis in cell culture. METHODS: Protein expression was visualised by tissue section immunostaining. RNA expression was analysed using Northern blot analysis. DNA synthesis of human vascular SMCs was determined by 3H-thymidine incorporation. Recombinant glutathione S-transferase-galectin-1 fusion protein (Gal FP) binding to extracellular matrix (ECM) proteins was measured by ELISA. Gal-1 binding to cells and ECM was estimated using 125I-labelled Gal FP. RESULTS: Prominent Gal-1 staining coincided with SMC proliferation in human coronary endarterectomy samples in organoid culture. In cell culture, Gal-1 mRNA was upregulated in growing SMCs. Gal FP increased serum-induced DNA synthesis of human SMCs on plastic or endogenous ECM, but not of a rat PAC1 SM cell line. Also, Gal FP slightly increased SMC adhesion to ECM. SMCs exhibited a complex pattern of receptor-ligand interactions with Gal FP. The Gal-1 binding to SMCs was much stronger than to ECM, produced by these SMCs. We identified new ECM proteins: thrombospondin, vitronectin and osteopontin, which bound to Gal FP in a dose- and beta-galactoside-dependent manner in ELISA. CONCLUSIONS: Gal-1 binding to SMCs was stronger than to ECM, although ECM of atherosclerotic blood vessels contained additional ECM proteins which bound to Gal-1. Gal-1 was upregulated during SMC growth and Gal FP enhanced serum-induced DNA synthesis in SMCs. Overall, Gal-1 upregulation is likely to provide a reinforcement of serum-induced events during vascular injury.

Arteriosclerosis↗
PubMed2000

In vitro evaluation of c7E3-Fab (ReoPro) eluting polymer-coated coronary stents.

OBJECTIVE: Stent thrombosis and in-stent restenosis remain problematic in certain patient sub-groups. c7E3-Fab (ReoPro, abciximab) inhibits the platelet glycoprotein IIb/IIIa receptor as well as the smooth muscle cell alpha(v)beta3 receptor, and thus may influence both processes, especially if high local concentrations could be achieved. We have studied the adsorption and elution characteristics of c7E3-Fab on commercially available polymer-coated stents. We have also investigated the effect of such antibody binding on platelet deposition in vitro, and on antibody deposition into ex vivo human saphenous vein wall to assess whether such stents may influence stent thrombosis and restenosis. METHODS AND RESULTS: Adsorption was measured using a radioisotope technique after immersing segments of polymer-coated stents in c7E3-Fab solutions. Uptake was dependent on antibody concentration and duration of immersion of wire in the solution. After 22 h (at 5 mg ml(-1)), 1146+/-101 ng cm(-1) wire was adsorbed. In an in vitro perfusion circuit, the antibody eluted slowly, with 53% remaining after 12 days washing. To determine the value that such stents might have in clinical practise, adsorption to balloon-mounted stents was assessed at room temperature, using commercially available c7E3-Fab (2 mg ml(-1)). Efficacy of eluting c7E3-Fab was determined by measuring deposition of 111-Indium platelets. Immersing stents in c7E3-Fab for 20 min inhibited platelet deposition by 82.3% compared to controls (P=0.018). Deployment of treated stents in ex vivo saphenous vein resulted in the deposition of c7E3-Fab in the intima and media. CONCLUSIONS: c7E3-Fab can be passively adsorbed onto polymer-coated stents. It elutes slowly and in a predictable manner, significantly inhibiting platelet deposition in vitro. These studies pave the way to developing stent-based delivery of a potent anti-platelet agent that may additionally affect smooth muscle cell activity.

Abciximab↗
PubMed2000

Inhibition of vascular smooth muscle cell adhesion and migration by c7E3 Fab (abciximab): a possible mechanism for influencing restenosis.

OBJECTIVES: Brief intravenous administration of chimeric antibody c7E3 Fab during coronary angioplasty has been shown in some studies to provide long term protection against coronary events. Smooth muscle cell (SMC) adhesion and migration are key initial steps in the development of restenosis. The purpose of this study was to investigate the effect of c7E3 Fab on adhesion and migration of SMC to the extracellular matrix (ECM) proteins osteopontin (Opn) and vitronectin (Vn). METHODS: Adhesion of human vascular SMCs to ECM proteins was quantified using a CyQUANT assay kit. Migration of SMCs to Vn, Opn and PDGF was studied using a modified Boyden's chamber migration assay. Integrin expression was determined by immunoprecipitation. RESULTS: c7E3 Fab reduced SMC adhesion on Vn and Opn to 69.2+/-3.3% (P<0.001) and 52.5+/-4.8% (P<0.001) respectively, compared to adhesion without antibody present. This reduction was the same as that for anti-alpha(v)beta(3) integrin antibody LM609 (P=0.5). The combination of anti-alpha(v)beta(5) integrin antibody and c7E3 Fab had a greater effect than either antibody alone (P<0.001). c7E3 Fab reduced SMC migration to Vn and Opn to 51.6+/-8.9% (P<0.001) and 20.3+/-6.1% (P<0.001) respectively, compared to migration in the absence of antibodies. Again, similar results were seen with LM609. PDGF-induced SMC migration was also inhibited by c7E3 Fab (P=0.004) and LM609 (P=0.001), but to much less an extent. The migration SMCs from a culture found not to express the alpha(v)beta(3) integrin was unaffected by these antibodies, strengthening the argument that c7E3 Fab inhibits SMC function via this integrin. CONCLUSIONS: c7E3 Fab inhibits the adhesion and migration of SMCs via the alpha(v)beta(3) integrin. The inhibition, however, is partial, and varied depending on type of ECM protein and alpha(v)beta(3) integrin expression. Some of the clinical benefits of c7E3 Fab may be due to its effect on SMCs.

Abciximab↗
PubMed2000

Inhibition of platelet thrombosis using an activated protein C-loaded stent: in vitro and in vivo results.

In high-risk and complicated coronary intervention, the risk of acute closure is unpredictable. Thrombus and platelet deposition at the intervention site may also have further effects on subsequent restenosis. In vivo infusion of activated protein C has previously been shown to achieve potent anticoagulation without any haemostatic side effects. We now evaluated the in vitro and in vivo efficacy of polymer-coated coronary stents loaded with purified rabbit Activated Protein C (APC). By measuring 125I-fibrinogen/fibrin deposition APC-loaded stent-wires were antithrombotic compared to albumin-loaded, inhibited-APC-loaded, plain polymer-coated and stainless steel stent-wires. In a balloon injury rabbit iliac artery model, APC-loaded stents did not occlude (0/14) compared to plain stents (9/15) and BSA-loaded stents (2/4). Relative 111In-labelled platelet deposition showed a similarly significant degree of inhibition. In conclusion, APC-loading could render stents significantly less thrombotic. Whether an effective antithrombogenic stent like this effectively reduces restenosis rates warrants further evaluation.

Adsorption↗
PubMed1999

Chronic haemoptysis as delayed complication of ventricular aneurysmectomy.

Two patients developed a ventriculo-pulmonary fistula several years after original resection of a left ventricular aneurysm. Both presented with chronic mild haemoptysis. In the first case mild haemoptysis lasted nearly 19 months, and despite a battery of non invasive and invasive investigations, diagnosis was ultimately made via exploratory thoracotomy. In the second case mild haemoptysis lasted four months and finally manifested as a large haemoptysis. Diagnosis was made preoperatively using echocardiography. We recommend the use of echocardiography when haemoptysis occurs in a patient with a previous history of ventricular aneurysm repair.

Aged↗
PubMed1999

Prognosis in myocardial infarction survivors with left ventricular dysfunction is predicted by electrocardiographic RR interval but not QT dispersion.

OBJECTIVES: The aim of the study was to assess if QT dispersion and RR interval on the standard 12-lead electrocardiogram (ECG) predict cardiac death and late arrhythmic events in postinfarction patients with low left ventricular ejection fraction (LVEF). QT dispersion on a standard electrocardiogram (ECG) is a measure of repolarization inhomogeneity, but its prognostic meaning in myocardial infarction (MI) survivors is unclear, especially in patients with left ventricular dysfunction. RR interval has been shown to predict mortality in post-MI patients, but its prognostic power has not been compared with other noninvasive risk factors. METHODS: Retrospective cohort study. Ninety patients were identified, from a series of 547 consecutive postinfarction patients admitted to our institution for phase II cardiac rehabilitation, as having a LVEF of <0.40 at two-dimensional echocardiography (mean LVEF 0.35+/-0.04; range 0.20-0.39). QT dispersion and RR interval were analyzed on the admission 12-lead electrocardiogram, 20+/-10 (range 8-45) days after MI, using specially designed software. Additional risk markers were collected from clinical variables, signal-averaged ECG and Holter recording. RESULTS: During 24+/-18 (range 1-63) months of follow-up, 10 of 90 patients (11%) died, all from cardiac causes, and there were 18 late arrhythmic events, defined as sudden death or the occurrence of a sustained ventricular arrhythmia > or =5 days after the index MI. QT interval and dispersion were not significantly prolonged in patients who died compared to survivors and not significantly different between patients with and without arrhythmic events. Mean RR interval from standard ECG was significantly shorter in patients with both cardiac death (682+/-99 vs. 811+/-134 ms; P=0.004) and arrhythmic events (720+/-100 vs. 818+/-139 ms; P=0.006). A Cox proportional hazards model identified RR interval from standard ECG (P<0.001) and a history of more than one MI (P=0.002) as significant predictors of cardiac death independent of thrombolytic therapy, LVEF, filtered QRS complex duration at signal-averaged ECG, mean RR and its standard deviation at 24-h Holter monitoring. CONCLUSIONS: Measurement of QT interval and dispersion 3 weeks after MI has no prognostic power in patients with LV dysfunction after a recent MI. RR interval on standard 12-lead ECG is as good a prognostic indicator as other, more expensive, noninvasive markers. These findings may be relevant in this era of limited health care resources.

Chi-Square Distribution↗
PubMed1999

Effect of an alpha(2) agonist (mivazerol) on limiting myocardial ischaemia in stable angina.

A specific alpha(2) agonist, mivazerol, known to be effective in reducing myocardial ischaemia when given intravenously immediately before an exercise tolerance test, produced a significant increase in exercise duration and time to the onset of angina when given orally over a two week period to 25 patients with stable angina. A non-significant trend to reduction in electrocardiographic signs of ischaemia was also noted. The clinical relevance of this improvement now needs to be tested in larger numbers.

Adrenergic alpha-Agonists↗
PubMed1998

Genetic identification of antigens exposed in damaged endothelial cells as laminin-binding proteins.

A monoclonal antibody, D5G2, which reacts in a balloon angioplasty damage model with unfixed damaged but not with unfixed undamaged human endothelial cells, was used to screen a human endothelial cDNA library in an Escherichia coli/lambda gt11 expression system. Sequences of DNA inserts in D5G2+ phage clones matched those reported for a laminin-binding protein, LBP-32. Both D5G2 and purified laminin bound to a polypeptide of 55 kD on PVDF membranes carrying electrophoretically separated endothelial cell lysates, D5G2 also bound to recombinant LBP expressed in E. coli, and showed similar staining patterns on human and bovine endothelial cells to another characterized anti-LBP antibody. Increased staining of unfixed endothelial cells on detergent permeabilization suggests that D5G2 binds to intracellular laminin-binding protein made accessible by cell membrane injury. Antibodies to intracellular targets exposed by cell damage may be useful in anchoring therapeutic agents at sites of vascular damage.

Angioplasty, Balloon↗
PubMed1998

A prioritisation system for elective coronary angiography.

OBJECTIVE: To devise a clinical prioritisation system for rationing access to a cardiac catheter waiting list and to describe its performance at predicting angiographic findings and selecting patients for angioplasty or coronary artery bypass graft surgery. SETTING: Tertiary level cardiology centre. METHODS: (1) 665 consecutive patients on an elective waiting list for coronary angiography were scored using a system derived from established clinical criteria for selecting patients for coronary surgery (New Zealand/Duke). The scores were compared with clinical outcome (referral for surgery, angioplasty, or medical management). (2) In a subset of 125 patients, scores derived from clinical criteria and exercise testing were compared with findings on coronary angiography. (3) Multivariate analysis was used in a new group of 178 patients to identify factors that would be better predictors of the angiographic score. (4) A new scoring system was devised based partly on the results of the multivariate analysis. It was applied to a new test group of 100 patients using clinical outcome and angiographic score as outcome measures. RESULTS: (1) Using the established clinical score, similar proportions of patients were referred after angiography for medical management, angioplasty, or coronary bypass grafting, irrespective of their original score. The exceptions were patients with a score < 20, who were more likely to continue medical management. (2) There was poor correlation (r = 0.05) between the clinical score and the subsequent angiographic score. (3) Multivariate analysis identified age, male sex, previous myocardial infarction, high cholesterol, and diabetes as independent predictors of coronary score. (4) The modified scoring system, incorporating the predictors identified by multivariate analysis, performed better than the original scoring system in predicting coronary score when both were tested, but some patients had severe disease despite a low score. CONCLUSIONS: Patients can be ranked using clinical and non-invasive criteria, and a rationing system implemented on this basis. With prioritisation by noninvasive criteria, the risk of missing serious coronary disease in patients with relatively mild symptoms must be accepted; this risk becomes greater the more stringently rationing is applied.

Aged↗
PubMed1997

Need for improved treatment for unstable coronary artery disease.

There is a pressing need for improved diagnosis and treatment of unstable coronary artery disease (UCAD). The limitations of the 12-lead electrocardiogram for diagnosing the disease are outlined in this article and additional diagnostic methods are discussed. Available treatments for UCAD are reviewed, including coronary bypass surgery, coronary angioplasty, and medical therapy. Finally, the issue of optimizing healthcare resources is discussed. It is concluded that preventing atheroma from entering an unstable phase may be the most cost-effective way of managing UCAD.

Coronary Angiography↗
PubMed1997

Cardiac rehabilitation services in England and Wales: a national survey.

We sent a short postal questionnaire to 244 centres in England and Wales that admitted patients with cardiac conditions. In total, 199 (81%) of the centres claimed to provide a cardiac rehabilitation service. Of these, 25 were randomly selected as a representative sample and visited in order to obtain detailed information concerning the provision of services. Most (18 (72%)) of the centres had commenced their rehabilitation programme within the previous 5 years, usually at the instigation of interested staff. Patient entry to cardiac rehabilitation programmes was restricted; women (who represented only 15% of attenders), elderly people (excluded in 10 (40%) centres), and those with more complex problems, such as angina or heart failure, were under-represented. The central components of all programmes were education and exercise training but there was a wide range in the quantity and quality of service provision. Most (22 (88%)) programmes were hospital out-patient based, one (4%) was hospital in-patient based, one (4%) was community-based and one (4%) was home-based. The staffing and funding of programmes was variable, with 7 (28%) having no identified funding. There are wide variations in the resources currently available for the rehabilitation of patients with coronary heart disease. There is a need for clearer direction of these services, in particular to determine minimum service provision. Guidelines are necessary to give a framework for this relatively new and rapidly expanding service.

Aged↗
PubMed1997

First myocardial infarction in patients of Indian subcontinent and European origin: comparison of risk factors, management, and long term outcome.

OBJECTIVE: To compare long term outcome after first myocardial infarction among British patients originating from the Indian subcontinent and from Europe. DESIGN: Matched pairs study. SETTING: Coronary care unit in central Leicester. SUBJECTS: 238 pairs of patients admitted during 1987-93 matched for age (within 2 years), sex, date of admission (within 3 months), type of infarction (Q/non-Q), and site of infarction. MAIN OUTCOME MEASURES: Incidence of angina, reinfarction, or death during follow up of 1-7 years. RESULTS: Patients of Indian subcontinent origin had a higher prevalence of diabetes (35% v 9% in patients of European origin, P < 0.001), lower prevalence of smoking (39% v 63%, P < 0.001), longer median delay from symptom onset to admission (5 hours v 3 hours, P < 0.01), and lower use of thrombolysis (50% v 66%, P < 0.001). During long term follow up (median 39 months), mortality was higher in patients of Indian subcontinent origin (unadjusted hazard ratio = 2.1, 95% confidence interval 1.3 to 3.4, P = 0.002). After adjustment for smoking, history of diabetes, and thrombolysis the estimated hazard ratio fell slightly to 2.0 (1.1 to 3.6, P = 0.02). Patients of Indian subcontinent origin had almost twice the incidence of angina (54% v 29%; P < 0.001) and almost three times the risk of reinfarction during follow up (34% v 12.5% at 3 years, P < 0.001). The unadjusted hazard ratio for reinfarction in patients of Indian subcontinent origin was 2.8 (1.8 to 4.4, P < 0.001). Adjustment for smoking, history of diabetes, and thrombolysis made little difference to the hazard ratio. Coronary angiography was performed with similar frequency in the two groups; triple vessel disease was the commonest finding in patients of Indian subcontinent origin and single vessel disease the commonest in Europeans (P < 0.001). CONCLUSIONS: Patients of Indian subcontinent origin are at substantially higher risk of mortality and of further coronary events than Europeans after first myocardial infarction. This is probably due to their higher prevalence of diffuse coronary atheroma. Their need for investigation with a view to coronary revascularisation is therefore greater. History of diabetes is an inadequate surrogate for ethnic origin as a prognostic indicator.

Coronary Angiography↗
PubMed1997

A new role for vascular endothelial growth factor and fibroblast growth factors: increasing endothelial resistance to oxidative stress.

Intracellular oxidative stress was measured in cultured human umbilical vein or bovine aortic endothelial cells exposed to hydrogen peroxide using an oxidation-sensitive vital dye, 2',7'-dichlorofluorescein, and flow cytometry. Vascular endothelial growth factor (VEGF), acidic fibroblast growth factor (aFGF) or basic fibroblast growth factor (bFGF) caused both a 5-10-fold increase in resistance to hydrogen peroxide induced fluorescence and an increase in intracellular reduced glutathione concentration. Increased resistance to oxidative stress mediated by growth factors is likely to be biologically relevant, and may open new avenues for therapeutic protection against oxidative stress.

Animals↗
PubMed1997

Can abnormalities of ventricular repolarisation identify insulin dependent diabetic patients at risk of sudden cardiac death?

OBJECTIVE: To study the possible association or QT dispersion and mean QTc intervals, as measured from standard 12 lead electrocardiograms, with baroreceptor-cardiac reflex sensitivity (BRS) in insulin dependent diabetic patients. DESIGN: Comparative study of non-invasive assessment of BRS, QT interval, and QT dispersion. SETTING: Large teaching hospital. SUBJECTS: 31 young asymptomatic, normotensive, insulin dependent diabetic patients, aged 20-55 years with normal clinical autonomic function. METHODS: QT intervals and QT dispersion were measured by a single observer blinded to other data about the patients. BRS was measured after activating the baroreflex with a Valsalva manoeuvre, and the rate in change of R-R interval to increasing systolic pressure during phase 4 was measured; in addition sequence analysis of resting systolic blood pressure and heart rate was performed during standing. The alpha coefficient--an index of the overall gain of the baroreflex mechanisms--was estimated from spectral analysis data of systolic blood pressure and pulse interval variability. RESULTS: Mean (SD) QTc interval was 406 (23) ms, QT dispersion was 44 (13) ms. There was no association between QT dispersion and any measurement of BRS. There was a negative correlation between mean QTc intervals and sequence analysis BRS (r = -0.355, P = 0.049), but no association with Valsalva BRS. The alpha coefficient, showed a significant negative correlation with mean QTc (r = -0.42, P = 0.008). CONCLUSIONS: Abnormal BRS may be reflected in the heart by global prolongation of ventricular repolarisation, but not by dispersion of ventricular repolarisation. This may, in part, explain the increase in sudden cardiac death seen in IDDM patients.

Adult↗